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Heiner WedemeyerDept. of Gastroenterology and Hepatology
Essen University Hospital
Hepatitis B (and D) Cure Strategies: How far are we?
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H. Wedemeyer 8-2018 Hepatitis Viruses
International Hepatitis E Symposium February 14-16, 2019
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H. Wedemeyer 10-2018 HBV cure
HBV is present in humans since >5.000
years (maybe 100.000 years) !
(isolation of HBV Genotype C2 from a
korean mummy 15th centruy)
Bar-Gal et al., Hepatology 2012
Paraskevis, Hatzakis et al.: Hepatology 2013 Mar;57(3):908-916
HBV Diversity in comparision to human evolution:
HBV infection of humans longer than 33.000 years!
Nature. 2018 May;557(7705):418-423. Ancient hepatitis B viruses from the Bronze Age to the Medieval period.
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H. Wedemeyer 10-2018 HBV cure
Hepatitis B Virus: Co-evolution over more than 400 Million years!
Lauber, Seitz, …. Bartenschlager; Cell Host Microbe 2017
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H. Wedemeyer 10-2018 HBV cure
The hepatitis B-associated disease burden is still increasing!
HBV-Cirrhosis Mortality
Increase 36%
HBV-HCC Mortality
Increase 51%
GBD-Study: Lancet Jan 2015
Cowie et al.: EASL 2015
Mortality due to HBV 2013~ 650.000
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H. Wedemeyer 10-2018 HBV cure
Hepatitis B ≠
Hepatitis B
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H. Wedemeyer 10-2018 HBV cure
Different phases of HBV infection
Lok, Zoulim et al., J Hepatology 2017
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H. Wedemeyer 10-2018 HBV cure
1Chang et al., Hepatology 2010 2Marcellin et al., Lancet. 2013 3Hosaka et al., Hepatology 2013, Kwon and Lok, Antivir Ther 2011Glebe & Bremer, Semin Liver Dis. 2013
Improvement of fibrosis1,2
NUCs
Suppression of HBV DNA in >95%
Reduction of risks for HCC and decompensation3
NA treatment of chronic hepatitis B
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H. Wedemeyer 10-2018 HBV cure
Papatheodoridis, GV et al., J. Hepatol. 2018; 68: 1129-1136
HBV NA-treated patients have an excellent longterm outcome!
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H. Wedemeyer 10-2018 HBV cure
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H. Wedemeyer 10-2018 HBV cure
Do we really need new therapies for hepatitis B?
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H. Wedemeyer 10-2018 HBV cure
➢HBsAg-positive patients have an increased risk to develop hepatocellular carcinoma
➢ Long-term treatment is associated with costs and may cause side-effects
➢ Immunosuppression may lead to severe HBV reactivation
➢Very limited treatment options for HDV coinfection
Why would “curative” therapies for HBV be useful?
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H. Wedemeyer 10-2018 HBV cure
Heterogeneity of hepatitis delta world-wide: the HDIN network
Hepatic clinical complications
➢ The Hepatitis Delta International Network (HDIN)➢ 1579 anti-HDV+ or HDV-RNA+ patients from 15 countries
Wranke et al., Liver International 2018
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H. Wedemeyer 10-2018 HBV cure
HDV infection increases the risk for liver-related clinical events
Beguelin et al., J Hepatol 2017 (66:297-303)
Anti-HDV+vs. anti-HDV(-)
HDV-RNA+vs. HDV-RNA(-)
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H. Wedemeyer 10-2018 HBV cure
PEG-IFNa leads to HDV RNA suppression in ~25% of cases
Wedemeyer, Yurdaydin et al. NEJM 2011
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H. Wedemeyer 10-2018 HBV cure
New treatments aiming for HBV cure
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H. Wedemeyer 10-2018 HBV cureLok, Zoulim et al., J Hepatology 2017
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H. Wedemeyer 10-2018 HBV cure
Source: Durantel & Zoulim. J Hepatol 2016; 64:117-131
DAA
HTA
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H. Wedemeyer 10-2018 HBV cure
HBV-specific T cells kill HBV infected cells
Kah, ..., Bertoletti, Dandri. Journal of Clinical Investigation 2017
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H. Wedemeyer 10-2018 HBV cure
Wooddell et al., Sci. Transl. Med. 2017
HBsAg-Reduction by siRNAs
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H. Wedemeyer 10-2018 HBV cure
Bazinet et al. Lancet G&H 2017
Nucleic Acid Polymers to block HBV release
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H. Wedemeyer 10-2018 HBV cure
Median HDV RNA levels
HBV-HDV Entry Inhibition
Wedemeyer et al., EASL 2018
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H. Wedemeyer 10-2018 HBV cure
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H. Wedemeyer 10-2018 HBV cure
The virological endpoint of novel therapies
HBsAg loss
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H. Wedemeyer 10-2018 HBV cure
Is HBsAg loss a reliable surrogate endpoint?
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H. Wedemeyer 10-2018 HBV cure
Jaroszewicz et al., Antiviral Therapy 2011
Loss of HBsAg during Nuc-Therapy can be predicted by HBsAg kinetics
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H. Wedemeyer 10-2018 HBV cure
HBsAg loss after 12 years of therapyJaroszewicz, Cornberg et al., AVT 2011
HCC2 years after HBsg loss
Is HBsAg loss a reliable surrogate endpoint?
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H. Wedemeyer 10-2018 HBV cure
HBsAg loss was not associated with a lower HCC incidence in Alaska!
Gounder et al., AP&T 2016
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H. Wedemeyer 10-2018 HBV cure
HCC rate / 100.000 person years:
HBsAg loss: 132
no HBsAG loss: 178
HR 0.7 (0.2-2.4); p=0.65
HBsAg loss was not associated with a lower HCC incidence in Alaska!
Gounder et al., AP&T 2016
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H. Wedemeyer 10-2018 HBV cure
Yuen et al., Gastroenterology 2008
Risk of HCC After HBsAg Loss
Follow-up (month)
Early loss of HBsAg is important
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H. Wedemeyer 10-2018 HBV cure
Lok, Zoulim et al., J Hepatology 2017
Potential Surrogate Markers for HBV: HBsAg
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H. Wedemeyer 10-2018 HBV cure
Different sources of HBsAgCornberg et al., J Hepatol 2017; 66:398-411
16
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H. Wedemeyer 10-2018 HBV cure
HBV-IntegrationMason et al., Gastroenterology 2016; 151: 986-998
• Integration randomly across chromosomes
• clonal hepatozyte-expansion high in high viremic infection
Similar data:Urban-lab (J Virol 2018)
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H. Wedemeyer 10-2018 HBV cure
Lok, Zoulim et al., J Hepatology 2017
Potential Surrogate Markers for HBV: HBV-RNA
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H. Wedemeyer 10-2018 HBV cure
Me
an
ch
an
ge
fro
m b
ase
line
(lo
g10
co
pie
s/m
L)
-2.0
-1.0
-0.5
0.0
0.5
-1.5
Cohort J(peg-IFN alpha-
2a +600 mg BD)
- 1.51
Cohort K(peg-IFN alpha-2a
+ placebo)
- 0.73
Cohort I(600 mg BD)
- 0.82
Placebo
HBV-RNA is induced by NVR 3-778
Yuen et al., EASL 2016 (LB06)
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H. Wedemeyer 10-2018 HBV cure
Lok, Zoulim et al., J Hepatology 2017
Potential Surrogate Markers for HBV: HBcrAg
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H. Wedemeyer 10-2018 HBV cure
HBcrAg in different phases of HBV infection
Higher Risk for reactivation?
Maasoumy, Cornberg et al., CMI 2015
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H. Wedemeyer 10-2018 HBV cure
Lok, Zoulim et al., J Hepatology 2017
Potential Surrogate Markers for HBV: cccDNA
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H. Wedemeyer 10-2018 HBV cure
Immunotherapies
New treatments for HBV
Host targeting agents Direct acting antivirals
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H. Wedemeyer 10-2018 HBV cure
…or simply to stop NA therapy?
New treatments for HBV
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H. Wedemeyer 10-2018 HBV cure
Stopping TDF-Treatment: The Gemran FINITE-StudyBerg, T et al., J. Hepatol. 2017; 67: 918–924
40
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H. Wedemeyer 10-2018 HBV cure
Induction of IP-10, IL12, TNFa, IL-10 and T-cell responses after cessation of therapy
Hoener zu Siederdissen, Rinker, et al. JID 2016
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H. Wedemeyer 10-2018 HBV cure
Stopping NA-Therapy leads to an immune induction„auto-vaccination“
Höner zu Siederdissen et al., J infect Dis 2016; 214: 1492-97Zimmer et al., J Infect Dis 2018; epub
Rinker et al., J Hepatol 2018 epub
43
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H. Wedemeyer 10-2018 HBV cure
How to use a new drug against HBV?
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Putative Target Profile for a New Curative Therapy for Hepatitis B
“The musts”
➢No major safety signal
➢Finite therapy ideally 12 weeks – 48 weeks (max)
➢Endpoint: HBsAg loss> 30% of patients (HBsAg decline sufficient?)
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HBsAg kinetics have to be consideredin the development of novel curative therapies
Antiviral Therapy
HBV DNA
HBsAgeraBicate
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Antiviral Therapy
HBV DNA
HBsAg
HBsAg kinetics have to be consideredin the development of novel curative therapies
Continue Therapy?Is this clinically meaningful?
eraBicate
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HBV DNA
HBsAg
Novel curative therapies as first line treatment?
Continue Therapy?Is this clinically meaningful?
eraBicate
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H. Wedemeyer: 02-2018
NK cells and T cells and HCV Therapy
Was kann der Patient noch tun?
Kaffee ist
gut
für die Leber
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H. Wedemeyer: 02-2018
NK cells and T cells and HCV Therapy
Is Aspirin good or bad?
Original InvestigationOctober 4, 2018
Association Between Aspirin Use and Riskof Hepatocellular Carcinoma
TraceyG. Simon, MD; Yanan Ma, PhD;Jonas F. Ludvigsson, MD, PhD;
et al
JAMA Oncology
Good: Lower HCC Incidence! Bad: Aspirin may cause cancer!
NEJM Sept 16 2018Effect of Aspirin on All-CauseMortality in the Healthy ElderlyJohn J. McNeil, et al.,for the ASPREE Investigator Group